Glucagon-like peptide-1 (GLP-1) is a gut hormone produced by intestinal endocrine L-cells in response to nutrient ingestion. GLP-1 inhibits glucagon secretion and stimulates glucose-dependent insulin release from the pancreas. It was observed that administration of GLP-1 significantly lowered blood glucose levels in Type II diabetes patients (Zander M, et al. Lancet 2002, 359: 824-830).
However, GLP-1, whether endogenously or exogenously administered, degrades rapidly. (Kieffer T. J., et al. Endocrinology 1995, 136: 3585-3596; and Mentlein R, et al. Eur. J. Biochem. 1993, 214: 829-839). The degradation is attributable to dipeptidyl peptidase IV (DPP-IV), a member of the prolyl peptidase family. Recent clinical data indicate that inhibiting DPP-IV resulted in enhanced insulin secretion, reduced plasma glucose concentrations, and improved pancreatic β-cell function (Pederson R. A., et al. Diabetes 1998, 47: 1253-1258; and Ahren B, et al. Diabetes Care 2002, 25: 869-875). Thus, inhibitors of DPP-IV are potential drug candidates for Type II diabetes.
Dipeptidyl peptidase VIII (DPP-VIII), another member of the prolyl peptidase family, is highly homologuous to DPP-IV. Some functions ascribed to DPP-IV have been found to derive from the activity of DPP-VIII (Rosenblum J. S., et al. Current Opinion in Chemical Biology 2003, 7: 496-504).